Posterior vitreous detachment and retinal tear - a prospective study of community referrals.

BACKGROUND: Retinal tears (RT) from posterior vitreous detachment (PVD) are an important and treatable cause of rhegmatogenous retinal detachment (RRD). Better understanding of the risk of RT from PVD will help plan urgent eye care. METHODS: Prospective observational case series over two years. Patients presenting to their optometrist, family doctor or emergency department with flashes and floaters were directed to a research clinic. History and examination, including slit-lamp biomicroscopy (SLB) and indentation indirect ophthalmoscopy (IIO), were performed by a single investigator, with two month follow-up for patients with confirmed PVD. Main outcome measures were incidence of PVD, RT, and RRD. RESULTS: 1010 patients were recruited. 896 (89%) patients had PVD at first assessment, of which 89 (8.8% of total cohort, 9.9% of PVD eyes) had RT and 8 had RRD. 21 (3%) of the remaining PVD patients developed RT in the subsequent two months and a further 9 (11%) patients with RT at initial assessment developed further tears by two months. 7 (0.7%) had asymptomatic RT in the fellow eye. 15% of RT were only visible on IIO and not SLB. Weiss ring was absent in 32% of eyes with RT. Patients with RT or RRD were more likely than 'PVD-only' eyes to have blurred or missing vision (p < 0.001), have higher rate of blue-green cataracts (p < 0.001), and longer axial lengths (p < 0.05). CONCLUSIONS AND RELEVANCE: This large, prospective study demonstrates a 9.9% rate of RT or RRD at the time of PVD, and emphasises the importance of IIO examination.

Use of vitreous phenotype as a key clinical marker to identify Ocular-only Stickler syndrome in a family with Marfan syndrome.

This clinical report describes a family with both Marfan and ocular-only Stickler syndromes. We report 2 cases of ocular-only Stickler syndrome and 2 cases of Marfan syndrome concurrent with ocular-only Stickler syndrome. Type 1 Stickler syndrome and Marfan syndrome share many clinical similarities, and it can be difficult to differentiate them solely based on clinical presentation. Vitreous phenotyping allows for the identification of vitreous anomalies pathognomonic of Stickler syndrome, which can guide future gene sequencing. Having the accurate diagnosis of Marfan or type 1 Stickler syndrome is important, as patients with type 1 Stickler syndrome have higher rates of retinal detachment and will benefit from prophylaxis.

Retinal detachment in Loeys-Dietz syndrome.

Loeys-Dietz syndrome (LDS) is an autosomal-dominant connective-tissue disorder with vascular and musculoskeletal abnormalities similar to Marfan syndrome. However, unlike Marfan, retinal detachment (RD) is rarely reported, and screening protocols do not currently feature ophthalmic assessment or RD counseling. We report a 5-generation family affected by LDS, where RD occurred in six eyes of four individuals. The proband was an 84-year-old male recently diagnosed with type-V LDS (TGFß3 pathogenic variant c.899G>A, p.(Arg300Gln)). Further investigation was undertaken into the family's medical history. The proband experienced bilateral rhegmatogenous RD at age 60, requiring emergency surgical repair. Other notable ophthalmic features include unusual keratometry, abnormal biometry, and severe hayfever requiring long-term sodium cromoglycate treatment. The proband's sister, father, and uncle had also experienced RDs, all prior to LDS diagnosis. This series demonstrates that RD risk may be significant in LDS, and on occasion the presenting clinical feature. We suggest ophthalmic examination should be added to the initial assessment LDS patients, and patients informed of the early warning symptoms of retinal detachment. As in Marfan syndrome, LDS patients may exhibit cornea plana and abnormal corneal topography, producing atypical biometry. They may also present with allergic conjunctivitis, and awareness of these signs might facilitate earlier diagnosis.

Autosomal Recessive Stickler Syndrome.

Stickler syndrome (SS) is a genetic disorder with manifestations in the eye, ear, joints, face and palate. Usually inherited in a dominant fashion due to heterozygous pathogenic variants in the collagen genes COL2A1 and COL11A1, it can rarely be inherited in a recessive fashion from variants in COL9A1, COL9A2, and COL9A3, COL11A1, as well as the non-collagen genes LRP2, LOXL3 and GZF1. We review the published cases of recessive SS, which comprise 40 patients from 23 families. Both homozygous and compound heterozygous pathogenic variants are found. High myopia is near-universal, and sensorineural hearing loss is very common in patients with variants in genes for type IX or XI collagen, although hearing appears spared in the LRP2 and LOXL3 patients and is variable in GZF1. Cleft palate is associated with type XI collagen variants, as well as the non-collagen genes, but is so far unreported with type IX collagen variants. Retinal detachment has occurred in 18% of all cases, and joint pain in 15%. However, the mean age of this cohort is 11 years old, so the lifetime incidence of both problems may be underestimated. This paper reinforces the importance of screening for SS in congenital sensorineural hearing loss, particularly when associated with myopia, and the need to warn patients and parents of the warning signs of retinal detachment, with regular ophthalmic review.

Homozygous Type IX collagen variants (COL9A1, COL9A2, and COL9A3) causing recessive Stickler syndrome-Expanding the phenotype.

Stickler syndrome (SS) is characterized by ophthalmic, articular, orofacial, and auditory manifestations. SS is usually autosomal dominantly inherited with variants in COL2A1 or COL11A1. Recessive forms are rare but have been described with homozygous variants in COL9A1, COL9A2, and COL9A3 and compound heterozygous COL11A1 variants. This article expands phenotypic descriptions in recessive SS due to variants in genes encoding Type IX collagen. Clinical features were assessed in four families. Genomic DNA samples derived from venous blood were collected from family members. Six affected patients were identified from four pedigrees with variants in COL9A1 (one family, one patient), COL9A2 (two families, three patients), and COL9A3 (one family, two patients). Three variants were novel. All patients were highly myopic with congenital megalophthalmos and abnormal, hypoplastic vitreous gel, and all had sensorineural hearing loss. One patient had severe arthropathy. Congenital megalophthalmos and myopia are common to dominant and recessive forms of SS. Sensorineural hearing loss is more common and severe in recessive SS. We suggest that COL9A1, COL9A2, and COL9A3 be added to genetic screening panels for patients with congenital hearing loss. Although recessive SS is rare, early diagnosis would have a high impact for children with potentially dual sensory impairment, as well as identifying risk to future children.

Bone morphogenetic protein 4 (BMP4) loss-of-function variant associated with autosomal dominant Stickler syndrome and renal dysplasia.

Stickler syndrome is a genetic disorder that can lead to joint problems, hearing difficulties and retinal detachment. Genes encoding collagen types II, IX and XI are usually responsible, but some families have no causal variant identified. We investigate a variant in the gene encoding growth factor BMP4 in a family with Stickler syndrome with associated renal dysplasia. Next generation sequencing of the coding region of COL2A1, COL11A1 and a panel of genes associated with congenital anomalies of the kidney and urinary tract (CAKUT) was performed. A novel heterozygous BMP4 variant causing a premature stop codon, c. 130G>T, p.(Gly44Ter), which segregated with clinical features of Stickler syndrome in multiple family members, was identified. No variant affecting gene function was detected in COL2A1 or COL11A1. Skin fibroblasts were cultured with and without emetine, and the mRNA extracted and analysed by Sanger sequencing to assess whether the change was causing nonsense-mediated decay. Nonsense-mediated decay was not observed from the extracted BMP4 mRNA. BMP4 is a growth factor known to contribute to eye development in animals, and gene variants in humans have been linked to microphthalmia/anophthalmia as well as CAKUT. The variant identified here further demonstrates the importance of BMP4 in eye development. This is the first report of a BMP4 DNA variant causing Stickler syndrome, and we suggest BMP4 be added to standard diagnostic gene panels for this condition.